Asthma is the most common chronic disease of childhood, with an economic burden that exceeds that of tuberculosis and HIV/AIDS combined. Epidemiologic evidence suggests that the origins of disease occur during pre-school years even when chronic symptoms appear in early adulthood. Moreover, several risk factors for childhood asthma suggest that the disease may have its beginnings already in utero, and the maternal milieu during pregnancy may contribute to disease risk. These data suggest that the trajectory to childhood asthma and related outcomes (e.g., allergic sensitization, wheeze) may begin prenatally, when maternal environmental exposures calibrate set points for responses to post-natal environmental cues. Our preliminary data (mostly collected in our birth cohort, the Infant Immune Study: IIS) suggest that mechanisms rooted in the environmental microbiome, the maternal immune milieu, the child's immune epigenome at birth and early-life microbiota play a prominent role in this trajectory: a) microbial community structure in house dust is associated with asthma-related outcomes; b) the maternal prenatal immune milieu (expressed as the ratio between the amounts of IFN? and IL13 produced by mitogen-stimulated maternal PBMC isolated during the third trimester of pregnancy) influences asthma risk in the child; c) DNA methylation in cord blood immune cells from IIS neonates is associated with the maternal prenatal immune milieu (IFN?:IL13 ratio) to which the child was exposed in utero; d) the neonatal methylome differs in children who do and do not become asthmatic by age 9, and SMAD3 hypermethylation predicts asthma selectively in children born to asthmatic mothers; e) neonatal microbiome perturbation is associated with significantly different relative risk of allergy at age 2 and asthma at age 4. The nature and chronology of these events lead us to hypothesize that the pregnant mother's immune profile, influenced by environmental exposures, modifies the child's epigenome in utero, postnatal airway microbiome development, and the trajectory to allergy and asthma during childhood. To test this hypothesis, we will leverage abundant existing information and well-characterized, banked samples from the IIS population. We propose to characterize the child's immune methylome at birth and its relationships with the prenatal maternal immune milieu (IFN?:IL13 ratio), respiratory microbiota development, and asthma and allergic disease outcomes from birth to age 9 yrs (Specific Aim 1); and to characterize environmental (house dust) microbial exposures and post-natal (<1 year old) respiratory microbiota and to assess their relationship with maternal prenatal immune profile, neonatal epigenome, and child's risk for asthma, allergy and related outcomes from birth to age 9 yrs (Specific Aim 2). To our knowledge, this is the first time that a single study examines all of these characteristics and their mutual relations in the context of childhood asthma and allergy. This proposal aims to fill this gap in knowledge to address the role of the hypothesized causal pathway in the development of childhood disease.